Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel

Pesce, Emanuela; Gorrieri, Giulia; Sirci, Francesco; Napolitano, Francesco; Carrella, Diego; Caci, Emanuela; Tomati, Valeria; Zegarra‐Moran, Olga; Bernardo, Diego di; Galietta, Luis J. V.

doi:10.1016/j.jcf.2016.02.009

Cited by 16 publications

(13 citation statements)

References 42 publications

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“…We performed functional analysis of Tα-1 activity as F508del-CFTR corrector by means of the microfluorimetric assay based on the HS-YFP that has been extensively used to investigate various rescue maneuvers (36)(37)(38)(39)(40) and by means of whole-cell patch-clamp analyses. In parallel, we also performed immunolocalization experiments and biochemical analyses of the electrophoretic mobility of the different CFTR forms expressed by the cells under resting conditions or following treatment with Tα-1.…”

Section: Discussionmentioning

confidence: 99%

“…F508del-CFTR CFBE41o-cells were subsequently engineered to stably express the halide-sensitive yellow fluorescent protein (HS-YFP). This cell line has been extensively used by our group to identify and characterize various CFTR modulators, including proteostasis regulators (36)(37)(38)(39)(40). CFBE41o-cells, coexpressing F508del-CFTR and HS-YFP, plated on 96-well plates, were treated for 24 hours with vehicle alone (DMSO), Tα-1 (25, 50, 100, or 200 ng/ml, all containing the same amount of DMSO), scrambled peptide (100 ng/ml, also containing DMSO), or cysteamine (250 μM).…”

Section: Tα-1 Does Not Increase F508del-cftr Expression/function In Pmentioning

confidence: 99%

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Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Section: Tα-1 Does Not Increase F508del-cftr Expression/function In Pmentioning

confidence: 99%

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

et al. 2018

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“…Likewise, Galietta and colleagues used connectivity mapping to identify drugs having a similar mode of action at the gene expression level as CFBE41o-and primary bronchial epithelial cells treated at 27 • C for 24 h [209]. Several anti-inflammatory glucocorticoids were found to increase Phe508del-CFTR function in the cell line, but the activity could not be confirmed in primary cells.…”

Section: Proteostasis Modulatorsmentioning

confidence: 99%

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub

McCray

2020

Genes

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Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

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“…low-temperature incubation, again seeking small molecules that mimic this rescue signature. 22 They identified several glucocorticoids that demonstrated rescue in CFBE cells, a widely used human airway epithelial cell line expressing ΔF508-CFTR, 23 but not in primary CF airway epithelial cells. Malcomson et al also used connectivity mapping to identify licensed drugs with TNFAIP3-induced anti-inflammatory effects.…”

Section: How Might This Change Drug Discovery Development And/ or Therapeutics?mentioning

confidence: 99%

Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508‐CFTR for cystic fibrosis

Hodos

Strub

Ramachandran

et al. 2021

CPT Pharmacom & Syst Pharma

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Rare diseases affect 10% of the first‐world population, yet over 95% lack even a single pharmaceutical treatment. In the present age of information, we need ways to leverage our vast data and knowledge to streamline therapeutic development and lessen this gap. Here, we develop and implement an innovative informatic approach to identify therapeutic molecules, using the Connectivity Map and LINCS L1000 databases and disease‐associated transcriptional signatures and pathways. We apply this to cystic fibrosis (CF), the most common genetic disease in people of northern European ancestry leading to chronic lung disease and reduced lifespan. We selected and tested 120 small molecules in a CF cell line, finding 8 with activity, and confirmed 3 in primary CF airway epithelia. Although chemically diverse, the transcriptional profiles of the hits suggest a common mechanism associated with the unfolded protein response and/or TNFα signaling. This study highlights the power of informatics to help identify new therapies and reveal mechanistic insights while moving beyond target‐centric drug discovery.

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Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel

Abstract: Our results suggest that rescue of F508del-CFTR by low temperature cannot be easily mimicked by small molecules and that compounds with closer transcriptional and functional effects need to be found.

Cited by 16 publications

References 42 publications

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508‐CFTR for cystic fibrosis

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